Heme metabolism mediates RANKL-induced osteoclastogenesis via mitochondrial oxidative phosphorylation

Area of Science:

• Cellular Metabolism
• Bone Biology
• Mitochondrial Function

Background:

• Osteoporosis affects over 200 million women annually, stemming from bone remodeling disorders.
• Osteoclast (OC) cellular metabolism is critical for understanding and treating osteoporosis.
• Mitochondrial biogenesis and function are implicated in OC activity.

Purpose of the Study:

• To investigate the role of mitochondrial biogenesis and heme metabolism in osteoclastogenesis.
• To explore the therapeutic potential of inhibiting heme synthesis for osteoporosis treatment.

Main Methods:

• Analysis of gene expression profiles in human and murine osteoclasts.
• Measurement of mitochondrial membrane potential (MMP).
• Inhibition of heme synthesis using genetic silencing and a pharmacological inhibitor (NMPP).
• In vivo studies using an ovariectomy-induced bone loss mouse model.

Main Results:

• RANKL stimulation induced mitochondrial biogenesis and activated heme synthesis pathways in OCs.
• Heme-related gene expression correlated with bone mineral density in human data.
• Inhibition of heme synthesis (Ferrochelatase silencing or NMPP) potently inhibited OC differentiation.
• NMPP treatment demonstrated a dose-dependent effect and efficacy in vivo, protecting against ovariectomy-induced bone loss.

Conclusions:

• RANKL signaling regulates mitochondrial formation and heme metabolism to support osteoclastogenesis.
• Targeting heme synthesis represents a novel therapeutic strategy for metabolic bone disorders like osteoporosis.